吸入麻醉药的临床药理学(英文)52张课件.ppt

1、Department of AnesthesiologyCivic CampusA note for those at the lecture Those I was able to keep awake might notice that Ive added/modified a couple of the slides to better reflect the information in the latest versions of your text books.Much the material on CV and RS effects can be annoyingly inco

2、nsistent between texts and editions For those who asked about“protection”and volatile anesthesia Ive appended a couple of recent articles“for your interest”“FYI”means that I wont examine you on this stuff but the Royal College might!This stuff is relatively new and part of a broader area of research

3、 in ischemic preconditioning you know,rat stuff Thanks for attending!Department of AnesthesiologyCivic CampusObjectives I Chemical structure Structure-function relationships Physiochemical properties Mechanism of action Pharmacokinetics of Inhaled Agents Uptake and Distribution Fa/Fi curves,and fact

4、ors which affect them Metabolism of Inhalation Anesthetics Department of AnesthesiologyCivic CampusObjectives II Definition of MAC Factors which affect MAC Cardiovascular effects Pulmonary effects CNS effects Neuromuscular effects Hepatic effects Renal effects Uterine effects Marrow effectsDepartmen

5、t of AnesthesiologyCivic CampusThe reality Theres an awful lot of stuff here-none of it is“new”All of it is in the textbooks Barash 4th Edition Chapter 15.Inhalation Anesthesia.377-417.Miller 5th Edition Chapter 3.Mechanisms of Action.48-73 Chapter 4.Uptake and Distribution.74-95 Chapter 5a.Cardiova

6、scular Pharmacology.96-124 Chapter 5b.Pulmonary Pharmacology.125-146 Chapter 6.Metabolism and Toxicity.147-173 Much of it requires rote memorization Some of it useful-all of it“test-able”I cant cover all of it in 3 hoursDepartment of AnesthesiologyCivic CampusGregs goals for this lecture Inflict my

7、view of what you should know Put this in a clinical(read:useful)context Explain that which needs explaining Leave the memory work to you Be back on my porch,beer in hand,by 1730Department of AnesthesiologyCivic CampusChemical structure INitrous OxideDiethyl EtherHalothaneDepartment of Anesthesiology

8、Civic CampusFun with chemistry Halogenation reduces flammability Fluorination reduces solubility Trifluorcarbon groups add stability Alkanes precipitate arrythmiasDepartment of AnesthesiologyCivic CampusChemical structure IIIsofluraneSevofluraneDesfluraneDepartment of AnesthesiologyCivic CampusPhysi

9、cal characteristics Please cram the contents of the appropriate table 15.1 from Barash 4th Ed the night before the exam.Take home points include:desflurane boils at 24 OC halothane is preserved with thymol vapor pressures are needed for some exam questions knowledge of blood:gas partition coefficien

10、ts may actually be useful Department of AnesthesiologyCivic CampusPartition coefficients Represent the relative affinity of a gas for 2 different substances(solubility)Measured at equilibrium so partial pressures are equal,but.The amounts of gas dissolved in each substance(concentration)arent equal.

11、We most commonly refer to blood:gas pc The larger the number,the more soluble in bloodDepartment of AnesthesiologyCivic CampusBlood:gas partition coefficientsAnesthetic Blood:Gas PC Desflurane 0.42 Nitrous oxide 0.46 Sevoflurane 0.65 Isoflurane 1.46 Enflurane 1.91 Halothane 2.50 Table 15-1.Barash 4t

12、h Edition.p378.Department of AnesthesiologyCivic CampusThe blood:gas pc is useful,really.Anesthesia is related to the partial pressure of the gas in the brain.If a drug is dissolved in blood,it isnt available as a gas More molecules of a soluble gas are required to saturate liquid phase before incre

13、asing partial pressure Speed of onset/offset closely related to solubility The lower the blood:gas pc-the faster the onsetDepartment of AnesthesiologyCivic CampusUptake and distribution Anesthesia depends upon brain partial pressure Alveolar partial pressure(PA)=Pbrain The faster PA approaches the d

14、esired level the faster the patient is anesthetized PA is a balance between delivery of drug to the alveolus and uptake of that drug into the blood Time for an analogyDepartment of AnesthesiologyCivic CampusTo induce anesthesia the bucket(PA)must be full.Unfortunately the bucket has a leak(uptake).T

15、o fill the bucket you must either(a)pour it in faster(increase delivery)or(b)slow down the leak(decrease uptake).abDepartment of AnesthesiologyCivic CampusFactors influencing delivery Alveolar ventilation Breathing system volume fresh gas flow Inspired partial pressure(PI)concentration effect second

16、 gas effectDepartment of AnesthesiologyCivic CampusConcentration and 2nd gas effectsDepartment of AnesthesiologyCivic CampusFactors influencing uptake Solubility(blood:gas pc)Cardiac output Alveolar-venous pressure gradient For those of you who like formulae:Uptake=Q (PA-Pv)/BP Department of Anesthe

17、siologyCivic CampusFA/FI CurvesDepartment of AnesthesiologyCivic CampusV/Q distribution and uptake Ventilation perfusion uptake is decreased which enhances rise in FA may speed induction for soluble agents less difference with low solubility agents(fast anyway)Department of AnesthesiologyCivic Campu

18、sNitrous Oxide N20 leaves blood 34x more than N2 absorbed Sure,other agents are more soluble but we dont give them at 70%end-tidal concentration distension of closed air spaces 70%N2O will double a pneumo in 10 minutesAgent Blood:Gas PC Nitrous Oxide 0.47 Nitrogen 0.014 Department of AnesthesiologyC

19、ivic CampusMechanism of Action Meyer-Overton Theory lipid soluble agent spreads membranes distorting membrane proteins(ie ion channels).Protein Receptor Hypothesis inhaled agent binds to membrane protein and changes ion conductance Neurotransmitter Availability inhaled agent prevents breakdown of GA

20、BA Gregs Postulate if more than one theory-then no one really knowsDepartment of AnesthesiologyCivic CampusMetabolism of inhaled anesthetics Fairly small component of elimination Occurs at cytochrome p450 Inducible Oxidative o-dealkylation dehalogenation epoxidation Reductive occurs only with haloth

21、ane in hypoxic conditionsDepartment of AnesthesiologyCivic CampusThree determinants of metabolism Chemical structure ether bond carbon-halogen bond Hepatic enzyme activity Blood concentrationDepartment of AnesthesiologyCivic CampusMetabolism of inhaled anesthetics IIAgent%metabolized Halothane 20 Se

22、voflurane 2-5 Enflurane 2.4 Isoflurane 0.2 Desflurane 0.02 Nitrous Oxide 0.004 Table 15-1.Barash 4th Edition.p378.Department of AnesthesiologyCivic CampusBreakDepartment of AnesthesiologyCivic CampusMinimum alveolar concentration Alveolar concentration required to prevent movement in 50%of subjects

23、standard stimulus represents brain concentration consistent within and between species additiveDepartment of AnesthesiologyCivic CampusMAC ValuesAgent MAC Nitrous oxide 104 Desflurane 6.6 Sevoflurane 1.8 Enflurane 1.63 Isoflurane 1.17 Halothane 0.75 Table 15-1.Barash 4th Edition.p378.Department of A

24、nesthesiologyCivic CampusFactors increasing MAC Hyperthermia Chronic ETOH abuse Hypernatremia Increased CNS transmitters MAOI Amphetamine Cocaine Ephedrine L-DOPATable 15.4.Barash 4th Edition.P389Department of AnesthesiologyCivic CampusFactors decreasing MAC Increasing age Hypothermia Hyponatremia H

25、ypotension(MAP50mmHg)Pregnancy Hypoxemia(38 mmHg)O2 content(I=D=S.Department of AnesthesiologyCivic CampusCardiac output Despite myocardial depression cardiac output is well-maintained with isoflurane and desflurane preservation of heart rate greater reduction in SVR preservation of baroreceptor ref

26、lexesDepartment of AnesthesiologyCivic CampusSystemic vascular resistance All are direct vasodilators,except N2O relax vascular smooth muscle cAMP-Ca2+and or nitric oxide involved variable effects on individual vascular bedsDepartment of AnesthesiologyCivic CampusDysrhytmias Halothane potentiates ca

27、techolamine-related dysrhythmias ED50 of epinehrine producing dysrhythmias at 1.25 MAC halothane 2.1 gkg-1 isoflurane 6.9 gkg-1 enflurane 10.9 gkg-1 Lidocaine doubles ED50 of epinephrine Children somewhat more resistantDepartment of AnesthesiologyCivic CampusCoronary blood flow Isoflurane is a poten

28、t coronary vasodilator In theory,dilation of normal coronary vessels can direct blood flow away from stenotic coronaries Steal-prone anatomy total occlusion of 1 major coronary vessel collateral perfusion with 90%stenosis In practice,doesnt seem to be a problemDepartment of AnesthesiologyCivic Campu

29、sRespiratory pattern Increased frequency Decreased tidal volume Decreased minute ventilation Attributed(in cats)to sensitization of pulmonary stretch receptors-not supported in humansDepartment of AnesthesiologyCivic CampusMechanoreceptors Sense tension in muscles/tendons in intercostal muscles Incr

30、eased resistance detected and increased respiratory effort recruited Responses to inspiratory and expiratory loads diminished Further inhibition in patients with COPDDepartment of AnesthesiologyCivic CampusChemoreceptors Apneic threshold raised Response to PCO2 blunted PCO2 increased while spontaneo

31、usly ventilating ED=IS=H hypoxic drive abolished by 0.1 MACDepartment of AnesthesiologyCivic CampusBronchial musculature Reduce vagal tone Direct relaxation increased cAMP(but not via adrenoreceptor mediated)When bronchospastic,a dose dependent reduction in Raw occurs with most agents Department of

32、AnesthesiologyCivic CampusHypoxic pulmonary vasoconstriction Inhaled anesthetics appear to blunt HPV and increase shunt Shunt and PO2 appear unchanged in studies of inhaled anesthetics during one lung ventilation Intrinsic changes in HPV confounded by changes in cardiac output pulmonary artery press

33、ure positionDepartment of AnesthesiologyCivic CampusCentral nervous system Increase cerebral blood flow Increase ICP Decreased CMRO2 Decreased frequency-increased voltage on EEG 2 MAC enflurane increases seizure activity Decreased amplitude-increased latency on SSEPDepartment of AnesthesiologyCivic

34、CampusNeuromuscular function Skeletal muscle relaxation Potentiate NDMR Trigger MHDepartment of AnesthesiologyCivic CampusHepatic Hepatic arterial blood flow decreased by halothane Clearance of drugs decreased in keeping with reductions in hepatic blood flow Hepatotoxicity mild,transient,postoperati

35、ve increase in LFTs?due to transient hypoxia reductive metabolites massive hepatic necrosis oxidative metabolite binds to hepatocyte repeat exposure leads to immune-mediated necrosisDepartment of AnesthesiologyCivic CampusRenal Dose-dependent decreases in renal blood flow glomerular filtration rate

36、urine output Related to changes in CO and BP not ADH Fluoride nephrotoxicity at serum conc.50 mol/l F-opposes ADH leading to polyuria methoxyflurane 2.5 MAC-hours enflurane 9.6 MAC-hours Department of AnesthesiologyCivic CampusObstetrical N2O has no effect Halogenated volatiles lead to dose-dependen

37、t uterine relaxation reductions in uterine blood flowDepartment of AnesthesiologyCivic CampusMiscellaneous N2O-related myelosupression if 12 hr exposure inhibition of methionine-synthetase megaloblastic anemia Inhaled anesthetics,N2O in particular,decrease leukocyte function Teratogenesis with prolonged exposure in rats Increased risk(RR=1.3)of spontaneous abortion with chronic exposure to N20 更多精品资请访问更多精品资请访问 更多品资源请访问更多品资源请访问